The aim of the current proposal is to supplement a clinical trial of brain stimulation for the treatment of patients with major depression by studying key variables that alter the effectiveness of the intervention. Repetitive transcranial magnetic stimulation (rTMS) is a treatment which was recently approved by the FDA for treatment resistant major depression (TRMD), i.e. patients who've failed to respond to multiple medications. CSP 556 is a nine site clinical trial that has been funded to evaluate rTMS effectiveness in the VA system. In order to administer the treatment, the rTMS stimulus generating equipment (coil) is placed over the patient's head to stimulate the dorsolateral prefrontal cortex region (DLPFC) of the brain. This stimulation induces focal magnetic fields to depolarize neurons in discrete cortical areas. Positioning the coil over the correct brain region and administering adequate stimulation intensity are critical for its antidepressant efficacy (Herbsman et al., 2009; George et al., 2010). The aim of this proposal is to maximize the knowledge gained from CSP 556 by studying key variables in coil positioning known to alter both these variables (accuracy in targeting DLPFC and intensity of stimulation). These coil position variables have been directly related to treatment outcomes. Results from this proposal could lead to an optimization of TMS delivery and improved care of depressed veterans. We chose to focus on two key aspects of coil position that alter antidepressant response: A) coil position along the scalp, which determines accuracy of brain location, B) distance of the coil from the underlying cortex, or skull to cortex distance (SCD), which is proportional to the magnetic field strength at the target brain region. We will calculate SCD based on the MRI image and correlate this value with change in the Hamilton Rating Scale for Depression (HRSD). Because VA patients have risk factors for cortical atrophy including advanced age, vascular risks (e.g. smoking), this SCD may be larger than in the civilian population and the stimulation intensity of the TMS may be inadequate to reach their cortex. With respect to the first variable, position along the scalp, the current standard of clinical practice is to position the TMS coil 5 cm anterior relative to the point at which stimulation induces a thumb twitch. A previous MRI study of coil position suggested that this 5 cm rule was not sufficiently anterior to reach DLPFC in 1/3 of the patients (Herbsman et al., 2009; George et al., 2010). In fact, the size of improvement in depressive symptoms (defined by a change in the HRSD) was associated with the degree to which the coil was placed anteriorly. CSP 556 improved upon prevailing clinical practices by positioning the coil 6 cm, and not 5 cm, from the location where TMS makes the thumb twitch. We propose to formally test the effectiveness of the 6 cm rule by examining whether a relationship between coil position and HRSD continues to exist. This would be an extension of the previous study conducted in patients treated with the 5 cm rule (Herbsman et al., 2009; George et al., 2010). MRI's will be collected on 120 patients in CSP 556 along with a marker to indicate on the MRI where the TMS coil was positioned during treatment. These images will be digitally warped to a standard space that will enable the correlation between anterior/posterior coil position and change in HRSD. We predict that this relationship will exist in the active and not the sham patients. It is also possible that a standar clinical rule will be inadequate to target stimulation and the 6 cm rule may also be inaccurate and MRI may be needed to improve accuracy. We will thus explore the potential benefit of more innovatively defined approaches to coil positioning by comparing change in HRSD to the distance of the stimulating coil from structural and functional MRI defined DLPFC. Finally, one of the missions of CSP 556 is to develop decision rules for when rTMS is cost effective (Naimark, Krahn, Naglie, Redelmeier, & Detsky, 1997). This proposal also augments CSP 556 by developing a decision rule for when adding MRI to assess coil position would be cost effective.